Project Summary Improving vascular health is a critical potential strategy to delay the onset of Alzheimer's disease (AD). However, there are few vascular targets as the specific mechanisms linking vascular dysfunction to AD remain unclear. Racial/ethnic minority groups in the United States have a higher vascular burden and more than a two-fold risk of developing Alzheimer's disease (AD). Further, recent data has confirmed that African-Americans also have a greater risk of having higher cerebral ?-amyloid (A?) burden than Whites. Yet, little work has been done to characterize the increased risk for AD among different racial/ethnic groups and little is known about `why' they carry a greater risk for AD. Arterial stiffness is emerging as a key vascular risk factor for late life dementia, through associations with various aspects of AD-related pathology including: cerebral small vessel disease, ?- amyloid deposition and brain atrophy in AD-prone regions. However, gaps in our understanding of this mechanism remain. To date, no existing studies have adequate data to directly connect arterial stiffness to aspects of AD pathology through its effects on cerebral blood flow or to evaluate the association in a multi-ethnic cohort. We propose to address these gaps in our knowledge by leveraging >15 years of highly detailed and unparalleled longitudinal vascular data from Multi-Ethnic Study of Atherosclerosis (MESA). The `MESA Multisite AD study' will add: a) repeated, detailed cognitive assessments to adjudicate cognition and assess cognitive changes over time; b) repeated MRIs to assess neurodegeneration, cerebrovascular disease and cerebral perfusion; and d) A?-PET imaging to quantify A? burden. The `MESA Multisite AD study' will contribute key findings and unique resources relating antecedent subclinical vascular disorders to AD pathology and cognitive decline. Specifically, it will address the role of changes arterial stiffness and hemodynamic pathways to AD- related pathology. This approach will be an efficient and cost-effective open-resource for researchers to identify antecedent modifiable vascular and metabolic risk factors (over >15 years) for AD and will help guide the development of novel therapeutic targets or prevention strategies for various forms of AD-related dementias.